Protease inhibitors

ABSTRACT

The present invention provides HIV protease inhibitors of formulas I, IA, IB, Ib or II, or pharmaceutically acceptable salts thereof, wherein R 2  may be, for example, 2-pyridyl-CH 2 —, 3-pyridyl-CH 2 —, 4-pyridyl-CH 2 —, a sulfonyl group as described in the formulas herein including benzenesulfonyl or thiophenesulfonyl groups, R 2a —CO)—, R 2a  being selected from the group consisting of piperonyl, 2-pyranzinyl (unsubstituted or substituted with H, or an alkyl of 1 to 4 carbon atoms) or a picolylamine group as described herein, wherein R3 may be, for example, a phenyl group or diphenylmethyl group as described herein, and wherein Cx may be, for example, COOH, CONR 5 R 6 , CH 2 OH or CH 2 OR 7 .

This application claims priority to U.S. Provisional Application No.60/846,084, filed Sep. 21, 2006, the entire contents of which are hereinincorporated by reference.

BACKGROUND OF THE INVENTION

Inhibitors of the HIV viral protease are presently considered the mosteffective drugs against HIV infection. Unfortunately, most currentproteases inhibitors are relatively large hydrophobic molecules thatpossess rather low bioavailability. A high pill burden is thereforerequired to attain the therapeutic dose in a patient. This is adeterrent, which too often results in patient non-compliance andinadequate treatment results. This situation leads to sub-optimaltherapeutic drug concentration that in turns leads to the development ofHIV resistant strains. Consequently, there is an urgent need to improvethe solubility and bioavailability of proteases inhibitors.

A unique class of amino acid based HIV protease inhibitors have beendescribed in international application No. PCT/CA02/00190 publishedunder No. WO02/064551 on Aug. 22, 2002 the entire content of which isincorporated herein by reference.

Aromatic derivatives have also been described in U.S. Pat. No. 6,632,816to Stranix et al, the entire content of which is incorporated herein byreference. This patent includes, more particularly, N,-synthetic aminoacid substituted L-lysine derivatives possessing potent aspartylprotease inhibitory properties. However, it would be advantageous toimprove these derivatives by enhancing aqueous solubility andbioavailability in order to reduce the pill burden and to favourpatient's compliance. Since it is challenging to generate activeprotease inhibitors, specifically toward wild-type and resistantstrains, the formation of derivatives of original HIV proteaseinhibitors such as inhibitors described in U.S. Pat. No. 6,632,816 toStranix et al, known to be active toward resistant strains represents aviable route with considerable advantages. More particularly, generationof compounds with enhanced aqueous solubility, bioavailability, time ofduration and formulation properties along with other advantages isdesirable in the development of an effective drug.

Compounds with improved solubility and bioavailability have beendescribed in U.S. application Ser. No. 10/902,935 published under No.2006-0025592A1 on Feb. 2, 2006 in the name of to Stranix et al. Thesecompounds were found to be suitable for oral administration in aqueoussolution.

SUMMARY OF THE INVENTION

The present invention provides new compounds which may be used toinhibit HIV protease.

More particularly, the present invention relates in a first aspectthereof to a compound of formula I

and pharmaceutically acceptable salt thereof,

where Cx may be selected, for example, from the group consisting ofCH₂OH, COOM′, CONR₅R₆, CH₂OR₇ where R₇ may be selected from the groupconsisting of (HO)₂P(O) and (MO)₂P(O), where M′ may be H or an alkalimetal or alkaline earth metal, where M may be an alkali metal oralkaline earth metal and a group of formula R_(7A)—CO—,

where R_(7A) may be selected, for example, from the group consisting ofa straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylgroup having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms inthe alkyl part thereof, an alkyloxy group of 1 to 6 carbon atom, —CH₂OH,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, aphenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

where X and Y, the same or different, may be selected, for example, fromthe group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆,—NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y togetherdefine an ethyleneoxy group of formula —OCH₂CH₂—, or —CH₂CH₂O—, or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O—, and an ethylenedioxy group offormula —OCH₂CH₂O—,

where R₁ may be selected, for example, from the group consisting of astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—,

where R₂ may be selected, for example, from the group consisting of H, astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms,2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,

a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, where R_(2A) may be selected from thegroup consisting of a straight or branched alkyl group of 1 to 6 carbonatoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkylgroup having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₁₀—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl (unsubstituted or substituted),3-pyridyl(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, alkyl of1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl,

a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

where X′ and Y′, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅,—SR₅, —COOR₅, —COR₅, —OCF₃, —CN and —CH₂OH,

wherein R₄ may be selected, for example, from the group consisting of H,a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,

where R₅ and R₆, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkylgroup of 3 to 6 carbon atoms,

where R₃ may be selected, for example, from the group consisting of acyclohexyl group of formula

a phenyl group of formula

a diphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII

In accordance with the present invention, R₂ may be selected, forexample, from the group consisting of 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, where R_(2A) may be selected from thegroup consisting of piperonyl, 2-pyrazinyl (unsubstituted or substitutedwith H, or an alkyl of 1 to 4 carbon atoms)

and a group selected from the group of

where X′, Y′, R₅, R₆ may be as defined herein.

In accordance with an exemplary embodiment of the present invention Cxmay be COOH.

In accordance with an additional embodiment the present invention Cx maybe CONR₅R₆.

In accordance with a further embodiment of the present invention, Cx maybe CH₂OH.

In accordance with yet a further exemplary embodiment of the presentinvention, Cx may be CH₂OR₇.

In accordance with an exemplary embodiment of the present invention, R₃may be a cyclohexyl group as described herein.

In accordance with an additional embodiment the present invention R₃ maybe a diphenylmethyl group as described herein.

In accordance with a further embodiment of the present invention, R3 maybe a naphthyl-CH₂ group as described herein.

In accordance with yet a further embodiment of the present invention, R3may be a phenyl group as described herein.

In accordance with the present invention R₃ may be a phenyl group offormula

where X′ or Y′ may be as defined herein and where at least one of X′ orY′ is, for example, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms.

Also in accordance with the present invention R₃ may be a phenyl groupof formula

Cx may be CH₂OR₇ and where R₇ may be selected, for example, from thegroup consisting of (HO)₂P(O) and (MO)₂P(O), wherein M may be an alkalimetal or alkaline earth metal and a group of formula.

Also in accordance with the present invention R₃ may be (C₆H₅)₂CH—,1-naphtyl-CH₂— or 2-naphthyl-CH₂—.

In an additional aspect, the present invention relates to a compound offormula IA

and pharmaceutically acceptable salt thereof,

where Cx may be selected, for example from the group consisting ofCH₂OH, COOM′, CONH₂, CONR₅R₆, CH₂OR₇ where R₇ may be selected, forexample, from the group consisting of (HO)₂P(O) and (MO)₂P(O), where M′may be H or an alkali metal or alkaline earth metal, wherein M may be analkali metal or alkaline earth metal and a group of formula R_(7A)—CO—,where R_(7A) may be, selected from the group consisting of a straight orbranched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, an alkyloxy group of 1 to 6 carbon atom, —CH₂OH, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—,CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl groupof formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

where X and Y, the same or different, may be selected, for example, fromthe group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆,—NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y togetherdefine an ethyleneoxy group of formula —OCH₂CH₂— or —CH₂CH₂O—, or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—,

where R₁ may be selected from the group consisting of a straight alkylgroup of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbonatoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in thecycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂— and 4-pyridyl-CH—,

where R₂ may be selected, for example, from the group consisting of H, astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms,2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,

a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

and a group of formula R_(2A)—CO—, R_(2A) may be selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl- (unsubstituted or substituted), 3-pyridyl-(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, or analkyl of 1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl,

a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

where X′ and Y′, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —CN, —OCF₃ and —CH₂OH,

where R₄ may be selected from the group consisting of H, a straightalkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,

where R₅ and R₆, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms,

In accordance with an embodiment of the invention, Cx may be selectedfrom the group consisting of COOH, and CONR₅R₆.

In accordance with the present invention, R₂ may be selected from thegroup consisting of 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,

a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, where R_(2A) may be selected from thegroup consisting of piperonyl, NR₅R₆(CH₂)_(m)—O—, 2-pyrazinyl(unsubstituted or substituted with H, or an alkyl of 1 to 4 carbonatoms), and a group selected from the group

In a particular embodiment of the present invention, R₂ may be selected,for example, from the group consisting of a benzenesulfonyl group offormula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

and a group selected from the group of formula

In a further aspect the present invention relates to a compound offormula IB

and pharmaceutically acceptable salt thereof,

where Cx may be selected, for example, from the group consisting ofCH₂OH, COOM′, CONH₂, CONR₅R₆, CH₂OR₇ where R₇ may be selected from thegroup consisting of (HO)₂P(O) and (MO)₂P(O), where M′ may be H or analkali metal or alkaline earth metal, where M may be an alkali metal oralkaline earth metal and a group of formula R_(7A)—CO—, where R_(7A) maybe selected, for example, from the group consisting of a straight orbranched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, an alkyloxy group of 1 to 6 carbon atom, —CH₂OH, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—,CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl groupof formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

where X and Y, the same or different, may be selected, for example, fromthe group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆,—NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y togetherdefine an ethylenoxy group of formula —CH₂CH₂O— or —CH₂CH₂O— or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—,

where R₁ may be selected, for example, from the group consisting of astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—,

where R₂ may be selected, for example, from the group consisting ofpiperonyl-CO—, 2-pyridyl-CO—, 3-pyridyl-CO—, 4-pyridyl-CO—,2-pyrazinyl-CO— (unsubstituted or substituted with H, or an alkyl of 1to 4 carbon atoms), a carboxyphenyl group of formula

and a pyridyl-CO— group selected from the group consisting of

where at least one of V and W may be a straight alkyl group of 1 to 6carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms and the other of V and W being,H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl groupof 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F,Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and—CH₂OH,

where X′ and Y′, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, and —CH₂OH,

where R₄ may be selected from the group consisting of H, a straightalkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,

where R₅ and R₆, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms.

In yet a further aspect the present invention relates to a compound offormula Ib

and pharmaceutically acceptable salt thereof,

where R₇ may be selected, for example, from the group consisting of(HO)₂P(O) and (MO)₂P(O), where M may be an alkali metal or alkalineearth metal and a group of formula R_(7A)—CO—, R_(7A) may be selectedfrom the group consisting of an alkyloxy group of 1 to 6 carbon atom,—CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, aphenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

where X and Y, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethylenoxy group of formula —CH₂CH₂O— or —OCH₂CH₂— or an alkylenedioxygroup selected from the group consisting of a methylenedioxy group offormula —OCH₂O— and an ethylenedioxy group of formula —OCH₂CH₂O—,

where R₁ may be selected, for example, from the group consisting of astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂— and 4-pyridyl-CH₂—,

where R₂ may be selected, for example, from the group consisting of H, astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms,2-pyridyl-CH₂—, 3-pyridyl-CH₁—, 4-pyridyl-CH₂—, a benzenesulfonyl groupof formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO— where R_(2A) may be selected, forexample, from the group consisting of a straight or branched alkyl groupof 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, acycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl partthereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxygroup of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₁,—CH₂CF₃, —CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl,4-morpholinyl, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—,(CH₃CH₂)₂N—, (CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—,C₆H₅CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl(unsubstituted or substituted with H or an alkyl of 1 to 4 carbonatoms), 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅,—OR_(S), —SR₅, —COOR₅, —COR₅, —CN, —OCF₃, and —CH₂OH,

wherein R₄ may be selected, for example, from the group consisting of H,a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,

and wherein R₅ and R₆, the same or different, may be selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms.

In an additional aspect, the present invention relates to a compound offormula II

and pharmaceutically acceptable salts thereof,

where Cx may be selected from the group consisting of CH₂OH, COOM′,CONH₂, CONR₅R₆, CH₂OR₇ where R₇ may be selected from the groupconsisting of (HO)₂P(O) and (MO)₂P(O), where M′ may be H or an alkalimetal or alkaline earth metal, where M may be an alkali metal oralkaline earth metal and a group of formula R_(7A)—CO—, where R_(7A) maybe selected from the group consisting of a straight or branched alkylgroup of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbonatoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in thecycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, an alkyloxy group of 1 to 6 carbon atom, —CH₂OH, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—,CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl groupof formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group of formula,

where X and Y, the same or different, may be selected, for example, fromthe group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆,—NHCOR₅, —OR₅, —SRS, —COOR₅, —COR₅, and —CH₂OH or X and Y togetherdefine an ethylenoxy group of formula —CH₂CH₂O— or —OCH₂CH₂— or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—,

wherein R₁ may be selected, for example, from the group consisting of astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,

wherein R₂ may be selected, for example, from the group consisting of H,a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms,2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, a benzenesulfonyl groupof formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, where R_(2A) may be selected from thegroup consisting of a straight or branched alkyl group of 1 to 6 carbonatoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkylgroup having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl (unsubstituted or substituted), 3-pyridyl(unsubstituted or substituted), 4-pyridyl- (unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, or analkyl of 1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl,

a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

where X′ and Y′, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₅, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —CN, —OCF₃ and —CH₂OH,

where R₄ may be selected from the group consisting of H, a straightalkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,

where R₅ and R₆, the same or different, may be selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms,

where R₈ may be selected from the group consisting of

a group selected from the group of

a group selected from the group of

a group of formula

and a group of formula

where R₃ may be selected from the group consisting of

a phenyl group of formula

a diphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII

The present invention further relates to the use of at least onecompound described herein for making a pharmaceutical composition,medicament or drug. The compound described herein may be used in themaking of a drug for the treatment and/or prevention of HIV infectionand/or for the prevention of the apparition of acquired immunodeficiencysyndrome (AIDS), and/or for reducing HIV replication and/or itscytopathic effects and/or inhibiting the HIV protease enzyme (e.g., forreducing the activity of an HIV protease) etc.

The present invention further relates to the use of the at least onecompound described herein for treating and/or preventing HIV infectionand/or AIDS for reducing HIV replication and/or its cytopathic effectsand/or inhibiting the HIV protease enzyme or else in an individual inneed thereof.

The invention also relates to a method of treating and/or preventing HIVinfection and/or AIDS (e.g., for delaying the apparition of AIDS), forreducing HIV replication and/or its cytopathic effects and/or forinhibiting the HIV protease enzyme or else in an individual in needthereof. In accordance with the present invention, the method maycomprise administering a compound described herein (or a pharmaceuticalcomposition, drug etc.) to (in) an individual in need thereof.

The present invention more particularly relates to a method of reducingthe replication of HIV, the method may comprise providing a cell with acompound described herein (or a pharmaceutical composition, drug etc.)or administering such compound to (in) an individual in need thereof.

The present invention also relates to a process or method for preparingthe compounds described herein and the use of intermediate compounds forsuch purpose.

The compounds of this invention may include pharmaceutically acceptablederivatives of the compounds as described herein. A “pharmaceuticallyacceptable derivative” means any pharmaceutically acceptable salt (e.g.,Na, K, Cs, etc), acetals (i.e., dimethylacetal, diethylacetal, etc),oxime, ammonium or ester (as for example, but not limited to methyl,ethyl, propyl, isopropyl esters, etc) of a compound of this invention.

Pharmaceutical compositions of this invention comprise any of thecompounds of the present invention, and pharmaceutically acceptablesalts thereof, with any pharmaceutically acceptable carrier, adjuvant orvehicle. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of this inventioninclude, but are not limited to ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethyleneglycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The pharmaceutical compositions of this invention may be administeredorally, parenterally by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. We prefer oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically acceptable carriers, adjuvants or vehicles. The term“parenteral” as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are amino acid, water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. Fatty acids, such as oleicacid and its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, such as Ph. Helv. or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspension and solutions. Inthe case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are administered orally, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax, and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene or polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters waxcetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable neat formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

Dosage levels of between about 0.01 and about 25 mg/kg body weight perday, preferably between about 0.5 and about 25 mg/kg body weight per dayof the active ingredient compound are useful in the prevention andtreatment of viral infection, including HIV infection. Typically, thepharmaceutical compositions of this invention will be administered fromabout 1 to about 5 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thepatient treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Preferably, such preparations contain from about 20% to about 80%active compound.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained. When thesymptoms have been alleviated to the desired level, treatment shouldcease. Patients may, however, require intermittent treatment on along-term basis, upon any recurrence of disease symptoms.

As the skilled artisan will appreciate, lower or higher doses than thoserecited above may be required. Specific dosage and treatment regimen forany particular patient will depend upon a variety of factors, includingthe activity of the specific compound employed, the age, body weight,general health status, sex, diet, time of administration, rate ofexcretion, drug combination, the severity and course of the infection,the patient's disposition to the infection and the judgment of thetreating physician.

It is to be understood herein, that if a “range” or “group ofsubstances” is mentioned with respect to a particular characteristic(e.g., temperature, concentration, time and the like) of the presentinvention, the present invention relates to and explicitly incorporatesherein each and every specific member and combination of sub-ranges orsub-groups therein whatsoever.

Thus, any specified range or group is to be understood as a shorthandway of referring to each and every member of a range or groupindividually as well as each and every possible sub-ranges or sub-groupsencompassed therein; and similarly with respect to any sub-ranges orsub-groups therein. Thus, for example,

-   -   with respect to the number of carbon atoms, the mention of the        range of 1 to 6 carbon atoms is to be understood herein as        incorporating each and every individual number of carbon atoms        as well as sub-ranges such as, for example, 1 carbon atoms, 3        carbon atoms, 4 to 6 carbon atoms, etc.

It is in particular to be understood herein that the compound formulaeeach include each and every individual compound described thereby aswell as each and every possible class or sub-group or sub-class ofcompounds whether such class or sub-class is defined as positivelyincluding particular compounds, as excluding particular compounds or acombination thereof; for example an exclusionary definition may read asfollows: “provided that when one of A and B is —COOH and the other is H,—COOH may not occupy the 4“position”.

The compounds of the present invention may be prepared usingconventional techniques from readily available starting materials. Thedetailed descriptions of these approaches are presented herein.

Schemes illustrate a generic example for the preparation of thecompounds described herein.

As it may be appreciated by the person skilled in the art, the abovesynthetic schemes are not intended to be a comprehensive list of allmeans by which the compound described and claimed in this applicationmay be synthesized but only represent exemplification of synthesismethods among others. Further methods will be evident to those ofordinary skill in the art.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

In the description herein, the following abbreviations are used:

Abbreviation Meaning Ac Acetyl AcOH Acetic acid APCI Atmosphericpressure chemical ionization AIDS Acquired Immunodeficiency Syndrome AZT3-Azido-3-deoxythymine (Zidovudine) Boc Benzyloxycarbonyl t-Butyltert-Butyl CAM Cerium ammonium molybdate DCM Dichloromethane DMAPN,N-dimethylaminopyridine DMSO Dimethylsulfoxide DMF DimethylformamideDNA Deoxyribonucleic acid EDAC1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride EtOAcEthyl acetate EtOH Ethyl alcohol g Gram h hour HIV-1, -2 Humanimmunodeficiency virus type 1, type 2 HOBt 1-Hydroxybenzotriazole HPLCHigh performance liquid chromatography HTLV-I, -II Human T-celllymphotropic virus type I, type II IL-2 Interleukin-2 Kg Kilogram LLiter LC-MS Liquid chromatography-mass spectrometry M Molar MeOH Methylalcohol mg Milligram mp Melting point min Minute Moc Methoxycarbonyl molMole mL Milliliter mmol Millimole nm Nanometer nM Nanomolar po OrallyrEPO Recombinant erythropoietin TLC Thin layer chromatography 3TC2′,3′-Dideoxy-3-thiacytidine TFA Trifluoroacetic acid THFTetrahydrofuran

DETAILED DESCRIPTION Examples

This section describes the synthesis of several compounds and theirprodrugs useful HIV aspartyl protease inhibitors. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

Materials and Methods

Analytical thin layer chromatography (TLC) was carried out with 0.25 mmsilica gel E. Merck 60 F₂₅₄ plates and eluted with the indicated solventsystems. Preparative chromatography was performed by flashchromatography, using silica gel 60 (EM Science) with the indicatedsolvent systems and positive air pressure to allow proper rate ofelution. Detection of the compounds was carried out by exposing elutedplates (analytical or preparative) to iodine, UV light and/or treatinganalytical plates with a 2% solution of p-anisaldehyde in ethanolcontaining 3% sulfuric acid and 1% acetic acid followed by heating.Alternatively, analytical plates can be treated with a 0.3% ninhydrinsolution in ethanol containing 3% acetic acid and/or a CAM solution madeof 20 g (NH₄)₆Mo₇O₂₄ and 8.3 g Ce(SO₄)₂ polyhydrate in water (750 mL)containing concentrated sulfuric acid (90 mL).

Preparative HPLC were perform on a Gilson apparatus equipped with a C18column, a 215 liquid handler module and 25 mL/min capacity head pumps.The HPLC is operated with a Gilson UniPoint System Software.

Semi-Preparative HPLC Conditions for Purification of Test Compounds:

HPLC system: 2 Gilson #305-25 mL pumps, Gilson #215 liquid handler forinjection and collection and a Gilson #155 UV-Vis absorbance detector,all controlled from a Gilson Unipoint V1.91 software

Column: Alltech (#96053) Hyperprep PEP, C-18, 100 Åα, 8 μm, 22×250 mm

Flow: 15 mL/min

Solvents: A; HO; B; CH₃CN

Gradient: 25% to 80% of B over 40 min

Detector: absorbance; λ; 210 & 265 nm

The crude material dissolved in acetonitrile to a concentration ofaround 50 to 80 mg/2 mL were injected in each run. Fractions werecollected in amounts of 9 mL pertaining absorbance was detected at theUV detector.

Unless otherwise indicated, all starting materials were purchased from acommercial source such as Aldrich Co. or Sigma Co.

Melting points (mp) were determined on a Büchi 530 melting pointapparatus in capillary tubes and were uncorrected.

Mass spectra were recorded on a Hewlett Packard LC/MSD 1100 system usingAPCI or electrospray sources either in negative mode or positive mode.

Nuclear magnetic resonance (NMR) spectra were recorded on a BrukerAMX-II-500 equipped with a reversed or QNP probe. Samples were dissolvedin deuterochloroform (CDCl₃), deuteroacetone (acetone-d₆),deuteromethanol (CD₃OD) or deuterodimethylsulfoxide (DMSO-d₆) for dataacquisition using tetramethylsilane as internal standard. Chemicalshifts (*) are expressed in parts per million (ppm), the couplingconstants (J) are expressed in hertz (Hz) whereas multiplicities aredenoted as s for singlet, d for doublet, 2d for two doublets, dd fordoublet of doublets, t for triplet, q for quartet, quint. for quintet, mfor multiplet, and br s for broad singlet.

DETAILED DESCRIPTION OF THE INVENTION General Procedures GeneralProcedure for the Preparation of Test Compounds

A. General Coupling Procedure with HOBt and EDAC

Method used in scheme 1 of this invention.

To the acid to be condensed (0.8 eq.) and 1-hydroxybenzotriazole (25 mg,0.18 mmol, 1.2 eq.) in solution in 1 mL of dichloromethane and few dropsof dimethylformamide, the minimum as to solubilize the reagents, wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(EDAC) (26 mg, 0.14 mmol, 0.9 eq). The mixture was stirred for 15 minbefore addition of the amine((1S)-4-amino-N-(4-amino-1-hydroxymethyl-butyl)-N-isobutyl-benzenesulfonamide(VII, example 1, step F)) (50 mg, 0.15 mmol) in 1 mL DMF. The resultingmixture was stirred for several hours, generally overnight, beforepouring into an extraction funnel containing 15 mL hydrochloric acid 1.0N and 30 mL ethyl acetate and extracted. The organic layers were washedwith 20 mL of water, dried over magnesium sulfate, filtered andevaporated. The crude mixture was purified by reverse phasesemi-preparative HPLC under the conditions described in the materialsand methods section. The fractions containing the desired compound werecombined and evaporated. The residue was taken up in a minimal amount ofacetonitrile, diluted with water and lyophilized.

B. General Coupling Procedure with HOBt and EDAC

Method used in scheme 2 of this invention.

To a suitable vessel was added 100 mg N-substituted amino acids, and a 1mL aliquot of DMF, 150 mg EDAC, 75 mg HOBt were added. After 30 min at40° C. 1.5 eq. of the amino amide/acid,(1S)-4-amino-N-(5-amino-1-carboxylamido-pentyl)-N-isobutyl-benzenesulfonamide(step D) was added along with 100 mg N-methyl morpholine. The solutionwas then stirred at 23° C. for 4-12 h. A 1M K₂CO₃ (20 mL aliquot) isadded and left for 1 h. Then, EtOAc is added (50 mL). The aqueous phaseis separated and extracted with citric acid (10%) 50 mL. The organicphase was separated and evaporated. The residue was purified bysemi-preparative HPLC and lyophilized.

C. Preparation of Amides and Sulphonamides Using Acid Chlorides andSulphonyl Chlorides

To the amine dissolved in dichloromethane and N,N-dimethylformamide(DMF), the minimum as to dissolve the product, were added 1.5 eq. ofdiisopropylethylamine and the mixture cooled in an ice bath understirring for 10-15 min. The acid/sulphonyl chloride (1.1 eq.) was addeddropwise and the reaction continued at 0° C. for 20-30 min and at roomtemperature an additional 2-4 hours. The reaction mixture was pouredinto an extraction funnel containing aqueous 1.0N sodium hydroxide andEtOAc and separated. The organic layer was washed with 1.0N hydrochloricacid, with brine, and then dried over magnesium sulfate. The crudeproduct obtained after evaporation was generally purified bysemi-preparative HPLC as described earlier (see materials and methodssection).

D. Alternative Procedure for the Preparation of Amide Derivatives fromAcid Chloride

In a dried flask and under nitrogen atmosphere, dry acetonitrile (1 mL),triethylamine (4 eq.) and N-hydroxybenzotriazole (1.2 eq.) were addedand stirred at room temperature. The corresponding acid chloride (1.1eq.) was added slowly and the mixture was stirred for 30 minutes. Theamine (product of example 8 (1 eq.) or other appropriate amine) was thenadded and the mixture was stirred until completion by TLC (100% EtOAc).The mixture was poured into an extracting funnel containing 50 mL ofethyl acetate. The organic layers were washed with water, saturatedNaHCO₃ and brine, dried over sodium sulfate, filtered and evaporated.The crude mixture was purified by flash chromatography with 100% AcOEt.

E. General Procedure for the Preparation of Amide Derivatives from Acid

N-Hydroxybenzotriazole (1.9 eq.),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC)(2.5 eq.) and the corresponding carboxylic acid (0.8 eq.) were added to1 mL of N,N-dimethylformamide and stirred at room temperature for 30-60minutes. The amine (product of example 8 (1 eq.) or other appropriateamine) was then added and the mixture was stirred until completion byTLC (100% EtOAc). The mixture was poured into an extracting funnel with50 mL of ethyl acetate. The organic layers were washed with water,saturated NaHCO₃ and brine, dried over sodium sulfate, filtered andevaporated. The crude mixture was purified by flash chromatography with100% EtOAc.

F. General Procedure for the Preparation of Secondary Amine Derivativesfrom Aldehydes

(5S)-2-Amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide(or the product of example 8 for the ornithine derivatives or otheramine) (1.0 eq.) was added to dichloromethane (1 mL) and stirred at 0°C. The corresponding aldehyde (1.0 eq.) and acetic acid (1.0 eq.) wereadded to the mixture. After stirring for 10 minutes, sodiumtriacetoxyborohydride (1.5 eq.) was added and the mixture stirred untilcompletion by TLC (100% EtOAc). The solvent was evaporated and the crudemixture was purified by reverse phase semi-preparative HPLC under theconditions described in the Materials and Methods section.

G. General Procedure for the Preparation of Carbamates from Alcohols

In a dried flask and under inert atmosphere, the alcohol was dissolvedin dry dichloromethane (0.2M) and dissuccinimidyl carbonate (1.0 eq.)was added. The mixture was stirred at room temperature for 2-3 hoursbefore addition of the solid amine. The mixture was stirred anadditional hour and then poured in an extraction funnel containing 1.0Nsodium hydroxide and ethyl acetate and extracted. The organic layer waswashed with a 1.0N hydrochloric acid solution (if the alcohol moiety donot bear a basic site) and with brine, dried with magnesium sulphate,filtered and evaporated to dryness. The crude residue was then purifiedby semi-preparative HPLC using the conditions described in the Materialsand Methods section.

EXAMPLES Step A. Preparation of (3S)-3-isobutylamino-azepan-2-one (IV)

L-α-amino-,-caprolactam (22.0 g) was dissolved in cold dichloromethane(DCM, 200 mL). isobutyraldehyde (12.6 g) was added slowly and stirreduntil the heat evolved was dissipated (water forms at the surface). Thecold solution was added to 46.5 g of powdered NaBH(OAc)₃ in DCM (0.5 L).AcOH (70 mL) was added to the solution. The slightly turbid mixture wasstirred at 20° C. for 4 h. A 500 mL solution of 2M NaOH was added slowlyto the turbid mixture and the pH adjust to 11 using a concentrated NaOHsolution, and then the mixture stirred for a further 20 min. Afterextraction, the DCM layer was dried with MgSO₄, filtered and evaporated.The oil thus obtained crystallizes slowly on standing (27.8 g, 85%) andwas used without further purification in the next step.

¹H NMR (CDCl₃): δ 0.93 (d, J=6.5, 3H), 0.97 (d, J=6.5, 3H), 1.39 (t,J=9.8, 1H), 1.47 (m, 1H), 1.78-1.65 (m, 2H), 2.00-1.93 (m, 2H), 2.32-2.2(m, 2H), 2.38 (t, J=9.7, 1H), 3.16 (m, 3H), 6.62 (s, 1H(NH)). mp 52-54°C. (hexanes).

A small sample was converted to the S-methyl benzyl urea by adding thesolid to a solution of S-methyl benzyl isocyanate in MeCN. NMR gives 98%ee

Step B. Preparation ofNα-isobutyl-Nα-(4-acetamidobenzenesulfonyl)-L-α-amino-,-caprolactam (V)

Nα-isobutyl-L-α-amino-,-caprolactam (IV) (4.1 g free base) was dissolvedin DCM (200 mL) and treated with 4.0 g triethylamine, followed by4-acetamidobenzenesulfonyl chloride (5.2 g). A 0.1 g portion ofdimethylaminopyridine was added and the mixture was stirred 5 h. Theresulting thick slurry was poured into 500 mL 0.5 M HCl and shakenvigorously. The solid in the biphasic solution was filtered out andwashed with cold acetone to give 7.3 g (87%) of clean product.

¹H NMR (DMSO-d₆): δ 0.93 (d, J=6.0, 3H), 0.96 (d, J=6.0, 3H), 1.39 (t,J=12.0, 1H), 1.85-1.65 (m, 3H), 2.08-2.18 (m and s, 6H), 2.90-2.97 (m,1H), 3.00-3.06 (m, 2H), 3.35 (dd, J=14.2, 8.5, 1H), 4.65 (d, J=8.7, 1H),6.3 (s, 1H), 7.42 (d, J=8.8, 2H), 7.6 (d, J=8.8, 2H). mp 230-233° C.(EtOH),

Step C. Preparation of(3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl-amino}-2-oxo-azepane-1-carboxylicacid tert-butyl ester (Boc activation) (VI)

4.2 g ofNα-isobutyl-Nα-(4-acetamidobenzenesulfonyl)-L-α-amino-,-caprolactam (V)was suspended in 30 mL MeCN and briefly sonicated to break up any largechunks. To this white suspension was added 6.7 g (3 eq.) ofdi-tert-butyl pyrocarbonate in 10 mL MeCN. The suspension was stirredwith a magnetic bar and a 120 mg portion of DMAP was added. The solutionbecomes a clear light yellow after a few minutes. TLC (EtOAc) reveals 1product Rf 0.9 (starting material Rf at 0.4). The solution is poured indistilled water 20 mL and extracted with ether, dried with Na₂SO₄ andevaporated yielding 6.90 g. A sample was recrystallized from hexanes.

¹H NMR (DMSO-d₆σ 0.68 (d, J=6.0, 3H), 0.85 (d, J=6.0, 3H), 1.39 (s,10H), 1.47 (s, 9H), 1.85-1.65 (m, 3H), 2.15 (s, 3H), 2.80 (q, J=4, 1H),3.10-3.36 (m, 2H), 4.01 (d, J=8.0, 1H), 4.85 (d, J=8.7, 1H), 7.32 (d,J=8.8, 2H), 7.87 (d, J=8.8, 2H). mp 123-124° C.

Step D. Preparation of(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(VII-deprotected) (reductive ring opening and deprotection)

A 3.0 g portion of(3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl-amino}-2-oxo-azepane-1-carboxylicacid tert-butyl ester (VI, step C) is dissolved in 40 mL EtOH followedby 750 mg NaBH₄. Brief heating with a heat gun gives a clear solution.TLC reveals one streaky spot after 20 min (EtOAc). The solution isconcentrated to a paste, poured in 40 mL 1N NaOH and extracted withethyl acetate, the organic phase dried with NaSO₄ and evaporated to give2.8 g of product intermediate (VII);(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (VII).

The above product intermediate is dissolved in 5 mL EtOH and 5 mL 12 NHCl is added. Vigorous gas evolution is observed for a few minutes.After 2 h the solution is evaporated and rendered basic withconcentrated KOH and extracted with EtOAc yielding 1.75 g of a whitepowder.

¹H NMR (DMSO-d₆): σ 0.82 (m, 6H), 0.97-1.12 (m, 2H), 1.15-1.30 (m, 3H),1.57 (m, 1H), 1.84 (m, 1H), 2.40 (t, J=7.8, 2H), 2.75 (m, 1H), 2.85 (m,1H), 3.21 (m, 1H), 3.44 (d, J=6.4, 2H), 5.92 (br s, 2H), 6.59 (d, J=8.0,2H), 7.39 (d, J=8.0, 2H).

Step A

The preparation of the title is based on scheme 4 of this invention.

(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamicacid tert-butyl ester (698 mg, 1.089 mmol) was added to 6 mL of ethanoland 6 mL of HCl. The mixture was stirred at room temperature untilcompletion by TLC. The ethanol was evaporated and the acidic mixture waspoured into an extracting funnel containing 75 mL of ethyl acetate and50 mL of HCl 1M and separated. The aqueous layer was washed with ethylacetate. The aqueous phase was basified with pellets of NaOH and pouredinto an extracting funnel. The organic layer was washed with NaOH 1M andbrine, dried over sodium sulfate, filtered, evaporated and dried undervacuum to give 544 mg (92%) of a yellow solid (Rf=0, 100% EtOAc,indicator: ninhydrin).

Step A, Preparation ofNα-isobutyl-Nα-(3,4-methylenedioxybenzenesulfonyl)-L-α-amino-,-caprolactam

(2S)-3-Isobutylamino-azepan-2-one (example 28, step A) 1.0 g wasdissolved in DCM (20.0 mL) and treated with 2 ml triethylamine followedby the addition of 3,4-methylenedioxybenzenesulfonyl chloride (900 mg).A 0.05 g portion of DMAP was added and the mixture was stirred 5 h. Theresulting solution was poured into mL 0.5 M HCl and shaken vigorously.The organic phase was dried and evaporated to give (1.30 mg) of cleanproduct.

¹H NMR (DMSO-d₆): * 0.93 (d, J=6.0, 3H), 0.96 (d, J=6.0, 3H), 1.26-1.47(m, 1H), 1.85-1.65 (m, 3H), 2.08-2.28 (m and s, 6H), 2.97-3.07 (m, 1H),3.11-3.33 (m, 3H), 4.65 (d, J=9.0, 1H), 6.02 (s, 2H), 6.88 (d, J=6.6,1H), 7.14 (s, 1H), 7.30 (d, J=6.7 1H).

Step B Specific Examples for the Preparation of Derivatives of GeneralFormula I

The following prodrugs were prepared from L-lysine derivatives using theprocedures summarized herein.

Example 1 Preparation of(1S,5S)-[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-bromo-phenyl)-ethyl]-carbamicacid methyl ester Step A. Preparation of(2S)-3-(2-bromo-phenyl)-2-methoxycarbonylamino-propionic acid (orL-Moc-2-bromophenylalanine)

1.0 g L-2-bromophenylalanine (Peptech Corp.) is dissolved in 6 mL 1MK₂CO₃ followed by 0.77 g methoxycarbonyloxysuccinimide in 20 mL acetone.The resulting clear biphasic solution is stirred for 4 h, thenconcentrated to 10 mL. The resulting basic solution is extracted withether and the aqueous phase rendered acidic with 6 M HCl. The oilyprecipitate is extracted with EtOAc (2×20 mL) and evaporated to yield1.16 g of a clear oil which crystallizes upon standing.

¹H NMR (CD₃OD): δ 2.94-3.02 (m, 1H), 3.30-3.36 (m, 1H), 3.51 (s, 3H)4.52 (t, J=7.6, 1H), 7.04 (t, J=6.8 1H), 7.20-7.26 (m, 2H), 7.52 (d,J=7.0, 2H).

Step B. Preparation of(1S,5S)-[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-bromo-phenyl)-ethyl]-carbamicacid methyl ester

This compound was prepared as for the preparation of the product ofexample 3 (step D) with 100 mg of L-Moc-2-bromophenylalanine (step A ofthis example). The resulting precipitated residue was further purifiedby reverse phase preparative HPLC. Yields 25 mg of the title compound.

LC-MS: 693.1 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.89-0.98 (m, 7H), 1.00-1.15 (m, 2H), 1.26-1.35 (m,2H), 1.45-1.52 (m, 1H), 1.62-1.70 (m, 1H), 1.88-1.95 (m, 1H), 2.74-2.98(m, 3H), 2.98-3.16 (m, 3H), 3.20-3.29 (m, 1H), 3.56 (s, 3H), 3.67-3.74(m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.39 (t, J=7.0, 1H), 6.75(d, J=8.0, 2H), 7.10-7.17 (m, 1H), 7.24 (s, 1H), 7.50 (d, J=8.0, 2H),7.58-7.61 (m, 1H).

³¹P NMR (CD₃OD): δ 2.75

Example 2 Preparation of (2S,2S) phosphoric acidmono-(2-[(4-aminobenzenesulfonyl)-isobutyl-amino]-6-{3-(2-bromo-phenyl)-2-[(2-methyl-pyridine-3-carbonyl)-amino]-propionylamino}-hexyl)ester

The title derivative was prepared as for the synthesis of the product ofexample 3 (step D) with 100 mg of3-(2-bromo-phenyl)-2-[(2-methyl-pyridine-3-carbonyl)-amino]-propionicacid. Yields 70 mg of the title compound. The3-(2-bromo-phenyl)-2-[(2-methyl-pyridine-3-carbonyl)-amino]-propionicacid starting material was easily prepared from the coupling ofL-2-bromophenylalanine (Peptech Corp.) and 2-methyl-nicotinoyl chloride.

LC-MS: 769.6 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.83-0.99 (m, 8H), 1.00-1.15 (m, 2H), 1.26-1.35 (m,2H), 1.45-1.52 (m, 1H), 1.62-1.70 (m, 1H), 1.88-1.95 (m, 1H), 2.84-2.98(m, 2H), 2.98-3.86 (m, 3H), 3.20-3.29 (m, 1H), 3.56 (s, 3H), 3.67-3.69(m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.99 (t, J=7.0, 1H), 6.68(d, J=8.0, 2H), 7.03-7.32 (m, 4H), 7.50 (d, J=8.0, 1H), 7.57 (t, J=7.8,1H), 7.71 (t, J=7.8, 1H), 8.43 (d, J=7.8 1H).

³¹P NMR (CD₃OD): δ 2.68

Example 3 Preparation of (2S,2S) phosphoric acidmono-(2-[(4-aminobenzenesulfonyl)-isobutyl-amino]-6-{3-(2-bromo-phenyl)-2-[(pyridine-4-carbonyl)-amino]-propionylamino}-hexyl)ester

This compound was done as for the preparation of the product of example3 (step D) with 100 mg ofL-3-(2-bromo-phenyl)-2-[(pyridine-4-carbonyl)-amino]-propionic acid. Theprecipitated residue was further purified by reverse phase preparativeHPLC. Yields 65 mg of the desired material. TheL-3-(2-bromo-phenyl)-2-[(pyridine-4-carbonyl)-amino]-propionic acidstarting material was easily prepared from the combination ofL-2-bromophenylalanine (Peptech Corp.) and isonicotinoyl chloride monohydrochloride (Aldrich).

LC-MS: 755.8 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.83-0.99 (m, 8H), 1.00-1.15 (m, 2H), 1.26-1.35 (m,2H), 1.45-1.52 (m, 1H), 1.62-1.70 (m, 1H), 1.88-1.95 (m, 1H), 2.84-2.98(m, 2H), 2.98-3.86 (m, 3H), 3.20-3.29 (m, 1H), 3.56 (s, 3H), 3.67-3.69(m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.99 (t, J=7.0, 1H), 6.68(d, J=8.0, 2H), 7.03-7.32 (m, 4H), 7.50 (d, J=8.0, 1H), 7.70 (d, J=7.8,2H), 8.73 (d, J=7.8 2H).

³¹P NMR (CD₃OD): δ 3.28

Example 4 Preparation of(1S,5S)-[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-fluoro-phenyl)-ethyl]-carbamicacid methyl ester

The title compound was synthesized as for the preparation of the productof example 3 (step D) with 100 mg ofL-3-(2-fluoro-phenyl)-2-methoxycarbonylamino-propionic acid (orL-Moc-2-fluorophenylalanine). Yields 14.5 mg 35% of the desiredmaterial. The L-3-(2-fluoro-phenyl)-2-methoxycarbonylamino-propionicacid starting material was easily prepared from the combination ofL-2-fluorophenylalanine (Peptech Corp.) andmethoxycarbonyloxysuccinimide as in example 4 (step A).

LC-MS: 647.2 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.90 (d, J=3.5, 6H), 0.95-1.01 (m, 1H), 1.02-1.11 (m,1H), 1.25-1.32 (m, 2H), 1.40-1.49 (m, 1H), 1.56-1.67 (m, 1H), 1.86-1.95(m, 1H), 2.82-2.90 (m, 1H), 2.90-2.96 (m, 2H), 2.98-3.03 (m, 1H),3.08-3.14 (m, 2H). 3.59 (s, 3H), 3.74-3.76 (m, 1H), 3.88-3.92 (m, 1H),4.02-4.06 (m, 1H), 4.33-4.35 (m, 1H), 6.74 (d, J=8.2, 2H), 7.04-7.12 (m,2H), 7.25-7.30 (m, 2H), 7.53 (d, J=8.2, 2H).

³¹P NMR (CD₃OD): δ 2.75

Example 5 Preparation of (1S,5S)[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-chloro-phenyl)-ethyl]-carbamicacid methyl ester

This derivative was made as for the preparation of the product ofexample 3 (step D) with 100 mg ofL-3-(2-chloro-phenyl)-2-methoxycarbonylamino-propionic acid (orL-Moc-2-chlorophenylalanine). Yields 71 mg of the desired material. TheL-3-(2-chloro-phenyl)-2-methoxycarbonylamino-propionic acid startingmaterial was easily prepared from the combination ofL-2-chlorophenylalanine (Peptech Corp.) andmethoxycarbonyloxysuccinimide as in example 4 (step A).

LC-MS: 664.3 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.89-0.98 (m, 8H), 1.00-1.15 (m, 2H), 1.26-1.35 (m,2H), 1.45-1.52 (m, 1H), 1.62-1.70 (m, 1H), 1.88-1.95 (m, 1H), 2.84-2.98(m, 2H), 2.98-3.06 (m, 3H), 3.20-3.29 (m, 1H), 3.56 (s, 3H), 3.67-3.69(m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.39 (t, J=7.0, 1H), 7.05(d, J=8.0, 2H), 7.16-7.25 (m, 3H), 7.34 (s, 1H), 7.75 (d, J=8.0, 2H).

³¹P NMR (CD₃OD): δ 2.47

Example 6 Preparation of (1S,5S)[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(4-bromo-phenyl)-ethyl]-carbamicacid methyl ester

This derivative was synthesized using the procedure described for thepreparation of(1S,5S)-[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-bromo-phenyl)-ethyl]-carbamicacid methyl ester (example 4, steps A and B) usingL-4-bromophenylalanine (Peptech Corp.) instead ofL-2-bromophenylalanine. The desired material was obtained in 28% yield(25 mg)

LC-MS: 707.0 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.90 (d, J=5.9, 6H), 1.00-1.17 (m, 2H), 1.20-1.30 (m,2H), 1.39-1.50 (m, 1H), 1.55-1.69 (m, 1H), 1.86-1.99 (m, 1H), 2.79-2.90(m, 2H), 2.91-3.11 (m, 4H), 3.59 (s, 3H), 3.75-3.79 (m, 1H), 3.86-3.92(m, 1H), 4.02-4.08 (m, 1H), 4.20-4.30 (m, 1H), 6.76 (d, J=8.2, 2H), 7.15(d, J=7.8, 2H), 7.42 (d, J=7.8, 2H), 7.54 (d, J=8.2, 2H).

³¹P NMR (CD₃OD): δ 2.74

Example 7

This compound was prepared based on Scheme 2

Preparation of(1S)-4-amino-N-(5-amino-1-carboxamido-pentyl)-N-isobutyl-benzenesulfonamide(reductive ring opening and deprotection)

A 3.0 g portion of(3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl-amino}-2-oxo-azepane-1-carboxylicacid tert-butyl ester (VI, step C) is dissolved in 40 mL EtOH followedby 1 mL NH₄OH_(conc). Brief heating with a heat gun gives a clearsolution. TLC reveals one streaky spot after 20 min (EtOAc). Thesolution is concentrated to a paste, poured in 40 mL 1N NaOH andextracted with ethyl acetate, the organic phase dried with NaSO₄ andevaporated to give 2.8 g of product intermediate;(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (VII).

The above product intermediate is dissolved in 5 mL EtOH and 5 mL 12 NHCl is added. Vigorous gas evolution is observed for a few minutes.After 2 h the solution is evaporated and rendered basic withconcentrated KOH and extracted with EtOAc yielding 1.75 g of a whitepowder.

100 mg portion of the above was added to a solution of 100 mg Moc-Dip in2 mL DMF containing 2 eq of EDAC and 1 eq HOBt. The solution was reactedfor 30 min and poured into 1 M K2CO3. The turbid solution was extractedwith EtOAc and the organic phase dried with Na2SO4 the evaporated todryness. The residue was then purified by RP-HPLC.

LC-MS: 638.3 (M+H)⁺, 95% pure

Example 8

This compound was prepared based on Scheme 2

As in example 7 using Acetyl-DIP.

LC-MS: 622.4 (M+H)⁺, 95% pure

Example 9

This compound was prepared based on Scheme 2

LC-MS: 667.4 (M+H)⁺, 95% pure

Example 10

This compound was prepared based on Scheme 2

LC-MS: 639.2 (M+H)⁺, 95% pure

Example 11

This compound was prepared based on Scheme 1 and 3

The compound was prepared from general procedure A using(2S)-2-tert-butoxycarbonylamino-2-naphthyl-propionic acid and(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(above) but the product was purified by flash chromatography yielding49% of the Boc derivative. This product was treated with trifluoroaceticacid to give the amine in 96% yield using the same conditions asdescribed for the preparation of(2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-2-naphthyl-propionamide.The product was used without further purification. The product wasreacted with benzene sulfonyl chloride using general procedure C.

LC-MS: 682.1 (M+H)⁺, 95% pure

Example 12

This compound was prepared based on Scheme 1 and 3

Prepared as in example 11 using 2-thiophene-sulphonyl chloride throughgeneral procedure C.

LC-MS: 688.1 (M+H)⁺, 95% pure

Example 13

This compound was prepared based on Scheme 1

LC-MS: 594.4 (M+H)⁺, 95% pure

Example 14

This compound was prepared based on Scheme 1

LC-MS: 623.4 (M+H)⁺, 95% pure

Example 15

This compound was prepared based on Scheme 1 and 3

LC-MS: 681.8 (M+H)⁺, 95% pure

Example 16

This compound was prepared based on Scheme 1

LC-MS: 697.9 (M+H)⁺, 95% pure

Example 17

This compound was prepared based on Scheme 1

LC-MS: 710.8 (M+H)⁺, 95% pure

Example 18

This compound was prepared based on Scheme 1 and 3

The compound was prepared from general procedure A using(2S)-2-tert-butoxycarbonylamino-2-bromophenyl-propionic acid and(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(above) but the product was purified by flash chromatography. Thisproduct was treated with trifluoroacetic acid to give the amine in 96%yield using the same conditions as described for the preparation of(2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-2bromophenyl-propionamide.The product was used without further purification. The product wasreacted with 3-hydroxy-2-methyl benzoic acid using general procedure E.

LC-MS: 704.8 (M+H)⁺, 95% pure

Example 19

This compound was prepared based on Scheme 1 and 3

As in example 18 using 6-hydroxy-2-picolinic acid through generalprocedure E

LC-MS: 691.8 (M+H)⁺, 95% pure

Example 20

This compound was prepared based on Scheme 1 and 3

The compound was prepared from general procedure A using(2S)-2-tert-butoxycarbonylamino-(2-methyl-phenyl)-propionic acid and(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(above) but the product was purified by flash chromatography. Thisproduct was treated with trifluoroacetic acid to give the amine in 96%yield using the same conditions as described for the preparation of(2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-(2-methyl-phenyl)propionamide.The product was used without further purification. The product wasreacted with nicotinic acid using general procedure E.

LC-MS: 610.8 (M+H)⁺, 95% pure

Example 21

This compound was prepared based on Scheme 1 and 3

As in example 20 using 6-methyl-nicotinic acid through general procedureE

LC-MS: 624.8 (M+H)⁺, 95% pure

Example 22

This compound was prepared based on Scheme 1 and 3

As in example 20 using 4-picolinic acid through general procedure E

LC-MS: 610.8 (M+H)⁺, 95% pure

Example 23

This compound was prepared based on Scheme 1 and 3

As in example 20 using 2-hydroxy-3-methyl benzoic acid through generalprocedure E

LC-MS: (M+H)⁺, 95% pure

Example 24

This compound was prepared based on Scheme 1 and 3

The compound was prepared from general procedure A using(2S)-2-tert-butoxycarbonylamino-(cyclohexyl)-propionic acid and(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(above) but the product was purified by flash chromatography. Thisproduct was treated with trifluoroacetic acid to give the amine in 96%yield using the same conditions as described for the preparation of(2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-(cyclohexyl)propionamide.The product was used without further purification. The product wasreacted with methyl chloroformate using general procedure C.

LC-MS: 639.8 (M+H)⁺, 95% pure

Example 25

This compound was prepared based on Scheme 1 and 3

As in example 24 using nicotinic acid through general procedure E

LC-MS: 602.8 (M+H)⁺, 95% pure

Example 26

This compound was prepared based on Scheme 1 and 3

As in example 24 using 6-methylnicotinic acid through general procedureE

LC-MS: 616.8 (M+H)⁺, 95% pure

Example 27

This compound was prepared based on Scheme 1

LC-MS: (M+H)⁺, 95% pure

Example 28

This compound was prepared based on Scheme 1

Preparation of (1S)-benzo[1,3]dioxole-5-sulfonic acid(5-amino-1-hydroxymethyl-pentyl)-isobutyl-amide

This compound was prepared fromNα-isobutyl-Nα-(3,4-methylenedioxybenzenesulfonyl)-L-α-amino-,-caprolactam(step A) in a three step reaction sequence (Boc activation, reductivering opening and deprotection) as described for the preparation of(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(example 28, steps C and D). The final product was obtained in 75% yieldand was used as such in the next step.

LC-MS: 717.8 (M+H)⁺, 95% pure

Example 29

This compound was prepared based on Scheme 1 and 3

The compound was prepared from general procedure A using(2S)-2-tert-butoxycarbonylamino-2-chlorophenyl-propionic acid and(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(above) but the product was purified by flash chromatography. Thisproduct was treated with trifluoroacetic acid to give the amine in 96%yield using the same conditions as described for the preparation of(2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-2-chlorophenyl-propionamide.The product was used without further purification. The product wasreacted with 4-picolinic acid using general procedure E.

LC-MS: 630.2 (M+H)⁺, 95% pure

Example 30

This compound was prepared based on Scheme 1 and 3

As in example 29 using 2-methylnicotinic acid through general procedureE

LC-MS: 645.2 (M+H)⁺, 95% pure

Example 31

This compound was prepared based on Scheme 1

LC-MS: 727.2 (M+H)⁺, 95% pure

Example 32

This compound was prepared based on Scheme 1

LC-MS: 652.3 (M+H)⁺, 95% pure

Example 33

This compound was prepared based on Scheme 1

Preparation of (3S)-3-(4-pyridylmethyl)lamino-azepan-2-one intermediatewas effected as in the synthesis (3S)-3-isobutylamino-azepan-2-one usingpyridine-4 carbaldehyde.

LC-MS: 660.3 (M+H)⁺, 95% pure

Example 34

This compound was prepared based on Scheme 1

LC-MS: 707.3 (M+H)⁺, 95% pure

Example 35

This compound was prepared based on Scheme 1

LC-MS: 681.8 (M+H)⁺, 95% pure

Example 36

This compound was prepared based on Scheme 1 and 3

As in example 18 using 3-methyl-2 picolinic acid through generalprocedure E

LC-MS: 689.3 (M+H)⁺, 95% pure

Example 37

This compound was prepared based on Scheme 1 and 3

As in example 18 using 3-hydroxy-4-methyl benzoic acid through generalprocedure E

LC-MS: 704.3 (M+H)⁺, 95% pure

Example 38

This compound was prepared based on Scheme 1 and 3

As in example 18 using 4-pyridine carbinol acid through generalprocedure G

LC-MS: 705.3 (M+H)⁴, 95% pure

Example 39

This compound was prepared based on Scheme 1 and 3

As in example 18 using 2-methyl nicotinic acid through general procedureE

LC-MS: 689.3 (M+H)⁺, 95% pure

Example 40

This compound was prepared based on Scheme 1 and 3

As in example 18 using 6-methyl nicotinic acid through general procedureE

LC-MS: 689.3 (M+H)⁺, 95% pure

Example 41

This compound was prepared based on Scheme 1 and 3

As in example 18 using 3,4 methylene dioxybenzoic acid through generalprocedure E

LC-MS: 718.3 (M+H)⁺, 95% pure

Example 42

This compound was prepared based on Scheme 1 and 3

As in example 18 using 4-picolinic acid through general procedure E

LC-MS: 675.3 (M+H)⁺, 95% pure

Example 43

This compound was prepared based on Scheme 1 and 3

As in example 18 using 5-methyl-pyrazine carboxylic acid through generalprocedure E

LC-MS: 690.3 (M+H)⁺, 95% pure

Example 44

This compound was prepared based on Scheme 1 and 3

As in example 18 using 2-pyrazine carboxylic acid through generalprocedure E

LC-MS: 676.3 (M+H)⁺, 95% pure

Example 45

This compound was prepared based on Scheme 1 and 3

As in example 18 using 2-pyridine carboxylic acid through generalprocedure E

LC-MS: 675.3 (M+H)⁺, 95% pure

Example 46

This compound was prepared based on Scheme 1 and 3

As in example 18 using nicotinic acid through general procedure E

LC-MS: 675.3 (M+H)⁺, 95% pure

Enzymatic Assay for Determining the Inhibition Constant (Ki) ofSynthetic Compounds Targeting the HIV Protease

This is a fluorometric assay based on the cleavage by protease of asubstrate carrying a donor group (EDANS) and an acceptor group (DABCYL)on each side of the cleavage site, interacting together throughfluorescence resonance energy transfer (FRET) as described by Matayoshiet al. (Science 247:954-954, 1990).

After calculation of Vo and Vi, the inhibition constant (Ki) of thecompound is determined using the equation of Henderson:

$\frac{Vo}{Vi} = {1 + \frac{\lbrack I\rbrack}{{Ki}_{app}}}$ Where${Ki} = \frac{{Ki}_{app}}{\frac{1 + \lbrack S\rbrack}{Km}}$

where Vo=the enzyme's initial velocity

Vi=the enzyme velocity in the presence of the inhibitory compound,

[I]=inhibitor concentration, [S]=substrate concentration,

Km=Michaelis-Menten constant and Ki_(app)=apparent Ki

Graphs are traced and the Ki determined using GraphPad Prism software v.3.0.

Anti-Viral and Cytotoxicity Assays In Vitro

-   -   To evaluate the EC₅₀ of our compounds, various drug        concentrations are incubated with the infected cell for six days        and then the metabolic activity of the cells is monitored by the        MTT assay. (See A. J. Japour et al., Antimicrobial Agents and        Chemotherapy, 37, 1095-1101, 1993 and R. Pauwels et al. Journal        of Virological Methods, 20, 309-321, 1988)    -   We use the laboratory viral strain NL4.3 as wild type virus and        the cell line used is MT-4 which is a T-cell line highly        sensitive to HIV-1. We also use some WT clinical strains. To        address the resistance issue we assay the inhibitors with NL4.3        mutants which are designed to be resistant to specific        commercially available inhibitors.    -   The same MTT assay is used to evaluate the CCIC₅₀ (cell culture        of IC₅₀) of our compounds except that the virus is omitted.

The compounds listed in Table 1 were prepared as indicated above. Thenumbers of the compounds listed in Table 1 (Ex. No.) corresponds to theexample numbers presented above.

The activities of the compounds are listed in Table 2, demonstratingtheir potential usefulness. The CCIC₅₀ are not shown in the table but itwas found that the average CCIC₅₀ for HIV protease inhibitors of theinvention was 30+/−20 M with a range of 6 to 100 μM. Ki, IC₅₀ and EC₅₀results for compounds of formula I are presented in Table 2,illustrating their potential usefulness.

TABLE 1 Structures of exemplary embodiments of HIV aspartyl proteaseinhibitors in accordance with this invention I

Ex. - D, L, DL No. X Y R₁ Cx R₂ R₃ R₄ n R, S, RS  1 H 4-NH₂ Iso-butyl-—CH₂O—(HO)₂P(O) CH₃O—CO 2-BrC₆H₄CH₂ H 4 S, S  2 H 4-NH₂ Iso-butyl-—CH₂O—(HO)₂P(O) 2-CH₃-3-pyridyl- CO 2-BrC₆H₄CH₂ H 4 S, S  3 H 4-NH₂Iso-butyl- —CH₂O—(HO)₂P(O) 4-Pyridyl-CO 2-BrC₆H₄CH₂ H 4 S, S  4 H 4-NH₂Iso-butyl- —CH₂O—(HO)₂P(O) CH₃O—CO 2-FC₆H₄CH₂ H 4 S, S  5 H 4-NH₂Iso-butyl- —CH₂O—(HO)₂P(O) CH₃O—CO 2-ClC₆H₄CH₂ H 4 S, S  6 H 4-NH₂Iso-butyl- —CH₂O—(HO)₂P(O) CH₃O—CO 4-BrC₆H₄CH₂ H 4 S, S  7 H 4-NH₂Iso-butyl- —CONH₂ CH₃O—CO (C₆H₅)₂CH H 4 S, S  8 H 4-NH₂ Iso-butyl-—CONH₂ CH₃—CO (C₆H₅)₂CH H 4 S, S  9 H 4-NH₂ Iso-butyl- —CONH₂4-Morpholine- Naphthyl-1-CH₂ H 4 S, S CO 10 H 4-NH₂ Iso-butyl- —COOHCH₃O—CO (C₆H₅)₂CH H 4 S, S 47 H 4-NH₂ Iso-butyl- —CH₂OH 3-O—CF₃-Naphthyl-2-CH₂ H 4 Benzenesulfonyl 48 H 4-NH₂ Iso-butyl- —CH₂OH

Naphthyl-2-CH₂ H 4 49 H 4-NH₂ Iso-butyl- —CH₂OH 2F-,4F- Naphthyl-2-CH₂ H4 Benzenesulfonyl 50 H 4-NH₂ Iso-butyl- —CH₂OH 3-MeO-4-MeO-Naphthyl-2-CH₂ H 4 benzenesulfonyl 51 H 4-NH₂ Iso-butyl- —CH₂OH

Naphthyl-2-CH₂ H 4 52 H 4-NH₂ Iso-butyl- —CH₂OH

Naphthyl-2-CH₂ H 4 53 H 4-NH₂ Iso-butyl- —CH₂OH 4 -CN- Naphthyl-2-CH₂ H4 Benzenesulfonyl 54 H 4-NH₂ Iso-butyl- —CH₂OH

Naphthyl-2-CH₂ H 4 55 H 4-NH₂ Iso-butyl- —CH₂OH

Naphthyl-2-CH₂ H 4 56 H 4-NH₂ Iso-butyl- —CH₂OH 2-Pyridyl-CH₂—Naphthyl-2-CH₂ H 4 57 H 4-NH₂ Iso-butyl- —CH₂OH Thiophene 2-SO₂(C₆H₅)₂CH H 4 58 H 4-NH₂ Iso-butyl- —CH₂OH benzenesulfonyl (C₆H₅)₂CH H 459 4-F 3-NH₂ Iso-butyl- —CH₂OH benzenesulfonyl Naphthyl-2-CH₂ H 4 60 4-F3-NH₂ Iso-butyl- —CH₂OH Thiophene 2-SO₂ Naphthyl-2-CH₂ H 4 61 H 4-NH₂Iso-butyl- —CH₂OH 3-Picolyl-NH—CO (C₆H₅)₂CH H 4 62 H 4-NH₂ Iso-butyl-—CH₂OH 4-Picolyl-NH—CO (C₆H₅)₂CH H 4 Ex. D, L, DL No. X/Y R₁ Cx R₂ R₃ R₄n R, S, RS 11 4-NH₂/H i-C₄H₉ —CH2OH C6H5SO2 Naphthyl-2-CH₂ H 4 S, S 124-NH₂/H i-C₄H₉ —CH2OH Thiophene 2-SO2 Naphthyl-1-CH₂ H 4 S, S 134-OCH2CH2-3 i-C₄H₉ —CH2OH CH₃O—CO 2-F-Phenyl-CH2 H 4 S, RS  14*

i-C₄H₉ —CH2OH CH₃O—CO 2-F-phenyl-CH2 H 4 S, S 15 4-OCH2CH2-3 i-C₄H₉—CH2OH 4-Morpholine-CO Naphthyl-1-CH₂ H 4 S, S 16 4-OCH2CH2O-3 i-C₄H₉—CH2OH 4-Morpholine-CO Naphthyl-1-CH₂ H 4 S, S 17 4-OCH2CH2-3 i-C₄H₉—CH2OH 4-Morpholine-CO 2-BrC₆H₄CH₂ H 4 S, S 18 4-NH₂/H i-C₄H₉ —CH2OH3-OH—2Me—Ph—CO 2-BrC₆H₄CH₂ H 4 S, S 19 4-NH₂/H i-C₄H₉ —CH2OH 6-OHpicoloyl 2-BrC₆H₄CH₂ H 4 S, S 20 4-NH₂/H i-C₄H₉ —CH2OH nicotinoyl2-Me—C₆H₄CH₂ H 4 S, S 21 4-NH₂/H i-C₄H₉ —CH2OH 6-Me-Nicotinoyl2-Me—C₆H₄CH₂ H 4 S.S 22 4-NH₂/H i-C₄H₉ —CH2OH 4-Pyridyl-CO 2-Me—C₆H₄CH₂H 4 S, S 23 4-NH₂/H i-C₄H₉ —CH2OH 2-OH-3-Me- 2-Me—C₆H₄CH₂ H 4 S, SPhenyl-CO 63 4-NH₂/H i-C₄H₉ —CH2OH 3-OH-4-Me- 2-Me—C₆H₄CH₂ H 4 S, SPhenyl-CO 24 4-NH₂/H i-C₄H₉ —CH2OH CH₃O—CO Cyclohexl-CH₂ H 4 S, S 254-NH₂/H i-C₄H₉ —CH2OH Nicotinoyl Cyclohexl-CH₂ H 4 S, S 26 4-NH₂/Hi-C₄H₉ —CH2OH 6-Me-Nicotinoyl Cyclohexl-CH₂ H 4 S, S 27 8-quinolinei-C₄H₉ —CH2OH CH₃O—CO (C₆H₅)₂CH H 4 S, S sulfonyl 28 3,4 methylenei-C₄H₉ —CH2OH 6-OH-picoloyl (C₆H₅)₂CH H 4 S, S dioxy 29 4-NH₂/H i-C₄H₉—CH2OH 4-Pyridyl-CO 2-Cl-Phenyl-CH₂ H 4 S, S 30 4-NH₂/H i-C₄H₉ —CH2OH2-Me-nicotinoyl 2-Cl-Phenyl-CH₂ H 4 S, S 31 3,4(—OCH2CH2O—) i-C₄H₉—CH2OH 4-Morpholine-CO (2-Br-Phenyl-CH₂ H 4 S, S 32 4-OCH2CH2-3 i-C₄H₉—CH2OH CH₃O—CO (C₆H₅)₂CH H 4 S, S 33 4-NH₂/H CH2-3-Pyridyl —CH2OHCH₃O—CO (C₆H₅)₂CH H 4 34 4-OCH2CH2-3 i-C₄H₉ —CH2OH 4-Morpholine-CO(C₆H₅)₂CH H 4 S, S  35*

i-C₄H₉ —CH2OH H (C₆H₅)₂CH H 4 S, S 36 4-NH₂/H i-C₄H₉ —CH2OH 3-Me-2-pyridyl-CO (2-Br-Phenyl-CH₂ H 4 S, S 37 4-NH₂/H i-C₄H₉ —CH2OH3-OH-4-Me- (2-Br-Phenyl-CH₂ H 4 S, S Phenyl-CO 38 4-NH₂/H i-C₄H₉ —CH2OH4-PicolylO—CO (2-Br-Phenyl-CH₂ H 4 S, S 39 4-NH₂/H i-C₄H₉ —CH2OH2-Me-Nicotinoyl (2-Br-Phenyl-CH₂ H 4 S, S 40 4-NH₂/H i-C₄H₉ —CH2OH6-Me-Nicotinoyl (2-Br-Phenyl-CH₂ H 4 S, S 41 4-NH₂/H i-C₄H₉ —CH2OHpiperonoyl (2-Br-Phenyl-CH₂ H 4 S, RS 42 4-NH₂/H i-C₄H₉ —CH2OH4-Pyridyl-CO (2-Br-Phenyl-CH₂ H 4 S, S 43 4-NH₂/H i-C₄H₉ —CH2OH 5-Me-2-Piperazinoly (2-Br-Phenyl-CH₂ H 4 S, S 44 4-NH₂/H i-C₄H₉ —CH2OH2-piperazine-CO (2-Br-Phenyl-CH₂ H 4 S, S 45 4-NH₂/H i-C₄H₉ —CH2OH2-pyridine-CO ((2-Br-Phenyl-CH₂ H 4 S, S 46 4-NH₂/H i-C₄H₉ —CH2OHnicotinoyl (2-Br-Phenyl-CH₂ H 4 S, S *corresponds to R8 in formula II

TABLE 2 Exemplary embodiments of further HIV aspartyl proteaseinhibitors. ANTI- KI_(—CALC) KI_(GRAPHIC) IC50 HIV- EN- EN- EN- EC50ZYME ZYME ZYME VIRAL HIV-1 HIV-1 HIV-1 STRAIN Object Protease ProteaseProtease NL4-3 ID Structure nM nM nM nM EX. 11

16.5 3200 EX. 12

 7.9 3000 EX 47

55.7 EX 48

 5.1 4.95  0.162 EX 49

54.6 EX 50

12.5 EX 51

26.2 EX 52

247.9  EX 53

37.4 EX 54

11.4 EX 55

<3.8 0.788 0.878 1375 EX 56

 4.9 5.898 >50000  EX 57

<3.8 0.541 0.601  64 EX 58

<3.8 0.492 0.436  61 EX 59

24.6 EX 60

10.5 >50000  EX 61

<3.8 0.473 0.465  171 EX 62

<3.8 0.443 0.51   170 EX. 7 

0.049 0.042 0.652 0.507  30 EX. 33

<3.8 1.007  196 EX. 8 

<3.8 1.073  238 EX. 9 

<3.8 0.572 0.58   70 EX. 10

0.79  1.08  >50000  EX. 44

0.318 0.471  60 EX. 45

0.429 0.615  197 EX. 46

0.119 0.372  58 EX. 41

0.05  0.336  43 EX. 42

<3.8 0.182 0.618  40 EX. 39

<3.8 0.183 0.58   70 EX. 40

<3.8 0.217 0.567  55 EX. 43

<3.8 0.491 0.836  135 EX. 2 This compound is the prodrug of EX 39

>300.0  EX. 1 This compound is a prodrug of an active compound describedin WO02/ 064551

>300.0  EX 3 This compound is a prodrug of EX 42

>300.0  EX 4 Prodrug

>300.0  EX 6 This compound is a prodrug of an active compound describedin WO02/ 064551

>300.0  EX 36

<3.8 0.267 0.503  204 EX 37

<3.8 0.224 0.683  60 EX 5 prodrug

91   EX 38

0.27  0.92   248 EX 18

0.26  0.6   136 EX 19

0.27  0.29   99 EX 13

 9.2 2135 EX 14

75.7 1832 EX 15

<3.8 0.788 0.995  524 EX 16

<3.8 2.024 >50000  EX 17

<3.8 1.000 1.026 0.599  665 EX 31

<3.8 3.659  980 EX 32

<3.8 0.781 0.899  151 EX 34

<3.8 0.821 0.963 1000 EX 35

<3.8 3.011 >50000  EX 27

<3.8 2.55   369 EX 28

0.47  EX 29

<3.8 3.81   144 EX 30

<3.8 2.15   422 EX 20

<3.8 1.417  148 EX 21

<3.8 1.286  198 EX 22

<3.8 1.353  158 EX 23

<3.8 4.122 >50000  EX 63

<3.8 0.938  165 EX 24

 5.3 5.212 >5000  EX 25

<3.8 2.876 >5000  EX 26

<3.8 3.314 >5000 

1. A compound of formula I

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is selected from the group consisting of CH₂OH, COOM′,CONR₅R₆, and CH₂OR₇, wherein R₇ is selected from the group consisting of(HO)₂P(O) and (MO)₂P(O), wherein M′ is H or an alkali metal or alkalineearth metal, wherein M is an alkali metal or alkaline earth metal and agroup of formula R_(7A)—CO—, R_(7A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atom, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethyleneoxy group of formula —OCH₂CH₂—, or —CH₂CH₂O—, or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O—, and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₁ is selected from the group consisting ofa straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atomsin the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of piperonyl, 2-pyrazinyl (unsubstituted or substituted withH, or an alkyl of 1 to 4 carbon atoms) and a group selected from thegroup of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —OCF₃, —CN and —CH₂OH, wherein R₄ is selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₅ and R₆, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms, wherein R₃ is selected from thegroup consisting of a cyclohexyl group of formula

a phenyl group of formula

a diphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII


2. (canceled)
 3. The compound of claim 1, wherein Cx is CH₂OH or CH₂OR₇.4. A compound of formula I

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is selected from the group consisting of COOM′, CONR₅R₆, andCH₂OR₇, wherein R₇ is selected from the group consisting of (HO)₂P(O)and (MO)₂P(O), wherein M′ is H or an alkali metal or alkaline earthmetal, wherein M is an alkali metal or alkaline earth metal and a groupof formula R_(7A)—CO—, R_(7A) being selected from the group consistingof a straight or branched alkyl group of 1 to 6 carbon atoms, acycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atom, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethyleneoxy group of formula —OCH₂CH₂—, or —CH₂CH₂O—, or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O—, and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₁ is selected from the group consisting ofa straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atomsin the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of H, a straight alkyl group of 1to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl(unsubstituted or substituted),3-pyridyl(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, alkyl of1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —OCF₃, —CN and —CH₂OH, and further wherein at least oneof X′ or Y′ is a straight alkyl group of 1 to 6 carbon atoms, a branchedalkyl group of 3 to 6 carbon atoms, or a cycloalkyl group of 3 to 6carbon atoms, wherein R₄ is selected from the group consisting of H, astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,wherein R₅ and R₆, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₃ is a phenyl group of formula


5. A compound of formula I

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is CH₂OR₇, wherein R₇ is selected from the group consistingof (HO)₂P(O) and (MO)₂P(O), wherein M is an alkali metal or alkalineearth metal, wherein X and Y, the same or different, are selected fromthe group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆,—NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y togetherdefine an ethyleneoxy group of formula —OCH₂CH₂—, or —CH₂CH₂O—, or analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O—, and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₁ is selected from the group consisting ofa straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atomsin the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of H, a straight alkyl group of 1to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl(unsubstituted or substituted),3-pyridyl(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, alkyl of1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —OCF₃, —CN and —CH₂OH, wherein R₄ is selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₅ and R₆, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms, wherein R₃ is a phenyl group offormula


6. The compound of claim 1, wherein R₃ is (C₆H₅)₂CH—, 1-naphthyl-CH₂—,or 2-naphthyl-CH₂—.
 7. A compound of formula IA

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is selected from the group consisting of CH₂OH, COOM′, CONH₂,CONR₅R₆, and CH₂OR₇, wherein R₇ is selected from the group consisting of(HO)₂P(O) and (MO)₂P(O), wherein M′ is H or an alkali metal or alkalineearth metal, wherein M is an alkali metal or alkaline earth metal and agroup of formula R_(7A)—CO—, R_(7A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atom, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethyleneoxy group of formula —OCH₂CH₂— or —CH₂CH₂O—, or an alkylenedioxygroup selected from the group consisting of a methylenedioxy group offormula —OCH₂O— and an ethylenedioxy group of formula —OCH₂CH₂O—,wherein R₁ is selected from the group consisting of a straight alkylgroup of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbonatoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in thecycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂— and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of H, a straight alkyl group of 1to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl-(unsubstituted or substituted),3-pyridyl-(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, or analkyl of 1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —N, —OCF₃ and —CH₂OH, wherein R₄ is selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₅ and R₆, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms.
 8. The compound of claim 7,wherein Cx is selected from the group consisting of COOH, and CONR₅R₆.9. The compound of claim 7, wherein R₂ is selected from the groupconsisting of 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, abenzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of piperonyl, NR₅R₆(CH₂)_(m)—O—, 2-pyrazinyl (unsubstitutedor substituted with H, or an alkyl of 1 to 4 carbon atoms), and a groupselected from the group


10. The compound of claim 9, wherein R₂ is selected from the groupconsisting of a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula


11. A compound of formula IB

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is selected from the group consisting of CH₂OH, COOM′, CONH₂,CONR₅R₆, and CH₂OR₇, wherein R₇ is selected from the group consisting of(HO)₂P(O) and (MO)₂P(O), wherein M′ is H or an alkali metal or alkalineearth metal, wherein M is an alkali metal or alkaline earth metal and agroup of formula R_(7A)—CO—, R_(7A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atom, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethylenoxy group of formula —CH₂CH₂O— or —CH₂CH₂O— or an alkylenedioxygroup selected from the group consisting of a methylenedioxy group offormula —OCH₂O— and an ethylenedioxy group of formula —OCH₂CH₂O—,wherein R₁ is selected from the group consisting of a straight alkylgroup of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbonatoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in thecycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of piperonyl-CO—, 2-pyridyl-CO—,3-pyridyl-CO—, 4-pyridyl-CO—, 2-pyrazinyl-CO— (unsubstituted orsubstituted with H, or an alkyl of 1 to 4 carbon atoms), a carboxyphenylgroup of formula

and a pyridyl-CO— group selected from the group consisting of

wherein at least one of V and W being a straight alkyl group of 1 to 6carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms and the other of V and W being,H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl groupof 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F,Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and—CH₂OH, wherein X′ and Y′, the same or different, are selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, and —CH₂OH, wherein R₄ is selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₅ and R₆, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms.
 12. A compound of formula Ib

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein R₇ is selected from the group consisting of (HO)₂P(O) and(MO)₂P(O), wherein M is an alkali metal or alkaline earth metal and agroup of formula R_(7A)—CO—, R_(7A) being selected from the groupconsisting of an alkyloxy group of 1 to 6 carbon atom, —CH₂OH, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—,CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl groupof formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethylenoxy group of formula —CH₂CH₂O— or —OCH₂CH₂— or an alkylenedioxygroup selected from the group consisting of a methylenedioxy group offormula —OCH₂O— and an ethylenedioxy group of formula —OCH₂CH₂O—,wherein R₁ is selected from the group consisting of a straight alkylgroup of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbonatoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in thecycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂— and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of H, a straight alkyl group of 1to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl (unsubstitutedor substituted with H or an alkyl of 1 to 4 carbon atoms), 2-quinolyl,3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, aphenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —CN, —OCF₃, and —CH₂OH, wherein R₄ is selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, and wherein R₅ and R₆, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms.
 13. A compound of formula II

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is selected from the group consisting of CH₂OH, COOM′, CONH₂,CONR₅R₆, and CH₂OR₇ wherein R₇ is selected from the group consisting of(HO)₂P(O) and (MO)₂P(O), wherein M′ is H or an alkali metal or alkalineearth metal, wherein M is an alkali metal or alkaline earth metal and agroup of formula R_(7A)—CO—, R_(7A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atom, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₅R₆, —NHCOR₅,—OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Y together define anethylenoxy group of formula —CH₂CH₂O— or —OCH₂CH₂— or an alkylenedioxygroup selected from the group consisting of a methylenedioxy group offormula —OCH₂O— and an ethylenedioxy group of formula —OCH₂CH₂O—,wherein R₁ is selected from the group consisting of a straight alkylgroup of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbonatoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in thecycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of H, a straight alkyl group of 1to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl (unsubstituted or substituted), 3-pyridyl(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, or analkyl of 1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —CN, —OCF₃ and —CH₂OH, wherein R₄ is selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₅ and R₆, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms, wherein R₈ is selected from thegroup consisting of a group selected from the group of

a group selected from the group of

a group of formula

and a group of formula

wherein R₃ is selected from the group consisting of a phenyl group offormula

a diphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII


14. A compound of formula I

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is CH₂OH, wherein X and Y, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN,—NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Ytogether define an ethyleneoxy group of formula —OCH₂CH₂—, or —CH₂CH₂O—,or an alkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O—, and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₁ is selected from the group consisting of2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂ isselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—,4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl(unsubstituted or substituted),3-pyridyl(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, alkyl of1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —OCF₃, —CN and —CH₂OH, and further wherein at least oneof X′ or Y′ is a straight alkyl group of 1 to 6 carbon atoms, a branchedalkyl group of 3 to 6 carbon atoms, or a cycloalkyl group of 3 to 6carbon atoms, wherein R₄ is selected from the group consisting of H, astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,wherein R₅ and R₆, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₃ is selected from the group consisting of acyclohexyl group of formula

a phenyl group of formula

a diphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII


15. A compound of formula I

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein Cx is CH₂OH, wherein X and Y, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN,—NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅, —COOR₅, —COR₅, and —CH₂OH or X and Ytogether define an ethyleneoxy group of formula —OCH₂CH₂—, or —CH₂CH₂O—,or an alkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O—, and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₁ is selected from the group consisting ofa straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atomsin the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, and 4-pyridyl-CH₂—, wherein R₂is selected from the group consisting of -2-pyridyl-CH₂—,3-pyridyl-CH₂—, 4-pyridyl-CH₂—, a benzenesulfonyl group of formula

a thiophenesulfonyl group of formula

a group selected from the group of

a group of formula

a group selected from the group of formula

and a group of formula R_(2A)—CO—, R_(2A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, piperonyl, pyrrolidinyl, piperidinyl, 4-morpholinyl,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl,4-hydroxyphenyl, 4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—,2-pyrrolyl, 2-pyridyl(unsubstituted or substituted),3-pyridyl(unsubstituted or substituted), 4-pyridyl-(unsubstituted orsubstituted), 2-pyrazinyl (unsubstituted or substituted with H, alkyl of1 to 4 carbon atoms), 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolylamine group selected from the group

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

a group selected from the group consisting of

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₅R₆, —NHCOR₅, —OR₅, —SR₅,—COOR₅, —COR₅, —OCF₃, —CN and —CH₂OH, and further wherein at least oneof X′ or Y′ is a straight alkyl group of 1 to 6 carbon atoms, a branchedalkyl group of 3 to 6 carbon atoms, or a cycloalkyl group of 3 to 6carbon atoms, wherein R₄ is selected from the group consisting of H, astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,wherein R₅ and R₆, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3to 6 carbon atoms, wherein R₃ selected from the group consisting of acyclohexyl group of formula

a phenyl group of formula

a diphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII


16. The compound of claim 1, wherein R₃ is a cyclohexyl group of theformula


17. The compound of claim 1, wherein R₃ is a phenyl group of the formula


18. The compound of claim 16, wherein Cx is CONR₅R₆.
 19. The compound ofclaim 18, wherein R₅ and R₆ are H.